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Biomolecules Dec 2023For more than 60 years, glutathione transferases (GSTs) have attracted attention, but the research field of the GSTome [...].
For more than 60 years, glutathione transferases (GSTs) have attracted attention, but the research field of the GSTome [...].
Topics: Glutathione Transferase; Glutathione
PubMed: 38136620
DOI: 10.3390/biom13121749 -
Biomolecules Apr 2023In humans, the cytosolic glutathione S-transferase (GST) family of proteins is encoded by 16 genes presented in seven different classes. GSTs exhibit remarkable... (Review)
Review
In humans, the cytosolic glutathione S-transferase (GST) family of proteins is encoded by 16 genes presented in seven different classes. GSTs exhibit remarkable structural similarity with some overlapping functionalities. As a primary function, GSTs play a putative role in Phase II metabolism by protecting living cells against a wide variety of toxic molecules by conjugating them with the tripeptide glutathione. This conjugation reaction is extended to forming redox sensitive post-translational modifications on proteins: S-glutathionylation. Apart from these catalytic functions, specific GSTs are involved in the regulation of stress-induced signaling pathways that govern cell proliferation and apoptosis. Recently, studies on the effects of GST genetic polymorphisms on COVID-19 disease development revealed that the individuals with higher numbers of risk-associated genotypes showed higher risk of COVID-19 prevalence and severity. Furthermore, overexpression of GSTs in many tumors is frequently associated with drug resistance phenotypes. These functional properties make these proteins promising targets for therapeutics, and a number of GST inhibitors have progressed in clinical trials for the treatment of cancer and other diseases.
Topics: Humans; COVID-19; Enzyme Inhibitors; Glutathione; Glutathione Transferase; Neoplasms
PubMed: 37189435
DOI: 10.3390/biom13040688 -
Archives of Razi Institute Apr 2022Increasing pieces of evidence have supported those chemicals from industrial, agricultural wastes and organoleptic activities play important role in the development of... (Review)
Review
Increasing pieces of evidence have supported those chemicals from industrial, agricultural wastes and organoleptic activities play important role in the development of neurological disorders. The frequency of neurological disorders is increased to a much extent in recent years with the advancements in science and technology. Google Scholar, PubMed, and Scopus databases were selected to search the relevant information by using keywords including "Heavy metals", "Neurotoxicity", "Glutathione", "Glutathione AND Neurodegenerative disorders" etc. Heavy metals are particularly recognized as a major resource of toxicities during the stage of early pregnancy where a fetus gets exposed to them from maternal activities and circulation. As infants have a weak immune system and cannot respond to the specific challenge as faced by the body during mercury, zinc, iron, and cadmium exposure. Daily diet and drinking habits in addition to industrial activities also form a major field of study under investigation. This study aims to investigate the role of these metals in the accumulation of pollutants in the brain, liver, and kidneys hence leading to serious consequences. Moreover, their prevalence in teenagers that are under the age of ten years is being observed that leads them to learn, writing, and intellectual abilities. Males are more affected due to their hormonal differences. The role of the GST gene in the development of cognitive conditions and its phenotypes has been discussed thoroughly in this review. The mutations of GST lead to the accumulation of peroxides and superoxides which exacerbate oxidative damage to cells. Binding of toxic metals to GSH genes and the role of glutathione transferase genes is was demonstrated in this review.
Topics: Pregnancy; Male; Female; Animals; Cadmium; Superoxides; Metals, Heavy; Glutathione; Glutathione Transferase; Mercury; Zinc; Environmental Pollutants; Iron
PubMed: 36284949
DOI: 10.22092/ARI.2021.356279.1816 -
Biomolecules Mar 2023Multidrug resistance is a significant barrier that makes anticancer therapies less effective. Glutathione transferases (GSTs) are involved in multidrug resistance...
Multidrug resistance is a significant barrier that makes anticancer therapies less effective. Glutathione transferases (GSTs) are involved in multidrug resistance mechanisms and play a significant part in the metabolism of alkylating anticancer drugs. The purpose of this study was to screen and select a lead compound with high inhibitory potency against the isoenzyme GSTP1-1 from (GSTP1-1). The lead compound was selected following the screening of a library of currently approved and registered pesticides that belong to different chemical classes. The results showed that the fungicide iprodione [3-(3,5-dichlorophenyl)-2,4-dioxo-N-propan-2-ylimidazolidine-1-carboxamide] exhibited the highest inhibition potency (ΙC = 11.3 ± 0.5 μΜ) towards GSTP1-1. Kinetics analysis revealed that iprodione functions as a mixed-type inhibitor towards glutathione (GSH) and non-competitive inhibitor towards 1-chloro-2,4-dinitrobenzene (CDNB). X-ray crystallography was used to determine the crystal structure of GSTP1-1 at 1.28 Å resolution as a complex with S-(p-nitrobenzyl)glutathione (Nb-GSH). The crystal structure was used to map the ligand-binding site of GSTP1-1 and to provide structural data of the interaction of the enzyme with iprodione using molecular docking. The results of this study shed light on the inhibition mechanism of GSTP1-1 and provide a new compound as a potential lead structure for future drug/inhibitor development.
Topics: Animals; Mice; Glutathione S-Transferase pi; Molecular Docking Simulation; Glutathione Transferase; Glutathione; Isoenzymes; Kinetics
PubMed: 37189361
DOI: 10.3390/biom13040613 -
World Journal of Gastroenterology May 2011Microsomal glutathione transferase (MGST1, EC 2.5.1.18) is a membrane bound glutathione transferase extensively studied for its ability to detoxify reactive... (Review)
Review
Microsomal glutathione transferase (MGST1, EC 2.5.1.18) is a membrane bound glutathione transferase extensively studied for its ability to detoxify reactive intermediates, including metabolic electrophile intermediates and lipophilic hydroperoxides through its glutathione dependent transferase and peroxidase activities. It is expressed in high amounts in the liver, located both in the endoplasmic reticulum and the inner and outer mitochondrial membranes. This enzyme is activated by oxidative stress. Binding of GSH and modification of cysteine 49 (the oxidative stress sensor) has been shown to increase activation and induce conformational changes in the enzyme. These changes have either been shown to enhance the protective effect ascribed to this enzyme or have been shown to contribute to cell death through mitochondrial permeability transition pore formation. The purpose of this review is to elucidate how one enzyme found in two places in the cell subjected to the same conditions of oxidative stress could both help protect against and contribute to reactive oxygen species-induced liver injury.
Topics: Endoplasmic Reticulum; Ethanol; Glutathione Transferase; Humans; Liver Diseases; Mitochondrial Membranes; Oxidative Stress; Reactive Oxygen Species
PubMed: 21633660
DOI: 10.3748/wjg.v17.i20.2552 -
Genome Biology 2002The soluble glutathione transferases (GSTs, EC 2.5.1.18) are encoded by a large and diverse gene family in plants, which can be divided on the basis of sequence identity... (Review)
Review
The soluble glutathione transferases (GSTs, EC 2.5.1.18) are encoded by a large and diverse gene family in plants, which can be divided on the basis of sequence identity into the phi, tau, theta, zeta and lambda classes. The theta and zeta GSTs have counterparts in animals but the other classes are plant-specific and form the focus of this article. The genome of Arabidopsis thaliana contains 48 GST genes, with the tau and phi classes being the most numerous. The GST proteins have evolved by gene duplication to perform a range of functional roles using the tripeptide glutathione (GSH) as a cosubstrate or coenzyme. GSTs are predominantly expressed in the cytosol, where their GSH-dependent catalytic functions include the conjugation and resulting detoxification of herbicides, the reduction of organic hydroperoxides formed during oxidative stress and the isomerization of maleylacetoacetate to fumarylacetoacetate, a key step in the catabolism of tyrosine. GSTs also have non-catalytic roles, binding flavonoid natural products in the cytosol prior to their deposition in the vacuole. Recent studies have also implicated GSTs as components of ultraviolet-inducible cell signaling pathways and as potential regulators of apoptosis. Although sequence diversification has produced GSTs with multiple functions, the structure of these proteins has been highly conserved. The GSTs thus represent an excellent example of how protein families can diversify to fulfill multiple functions while conserving form and structure.
Topics: Arabidopsis; Arabidopsis Proteins; Genome, Plant; Glutathione Transferase; Multigene Family; Protein Structure, Tertiary
PubMed: 11897031
DOI: 10.1186/gb-2002-3-3-reviews3004 -
International Journal of Biological... 2022As a superfamily of multifunctional enzymes that is mainly associated with xenobiotic adaptation, glutathione S-transferases (GSTs) facilitate insects' survival under... (Review)
Review
As a superfamily of multifunctional enzymes that is mainly associated with xenobiotic adaptation, glutathione S-transferases (GSTs) facilitate insects' survival under chemical stresses in their environment. GSTs confer xenobiotic adaptation through direct metabolism or sequestration of xenobiotics, and/or indirectly by providing protection against oxidative stress induced by xenobiotic exposure. In this article, a comprehensive overview of current understanding on the versatile functions of insect GSTs in detoxifying chemical compounds is presented. The diverse structures of different classes of insect GSTs, specifically the spatial localization and composition of their amino acid residues constituted in their active sites are also summarized. Recent availability of whole genome sequences of numerous insect species, accompanied by RNA interference, X-ray crystallography, enzyme kinetics and site-directed mutagenesis techniques have significantly enhanced our understanding of functional and structural diversity of insect GSTs.
Topics: Animals; Xenobiotics; Glutathione Transferase; Insecta; Glutathione; Amino Acids; Multifunctional Enzymes
PubMed: 36263171
DOI: 10.7150/ijbs.77141 -
Environmental Science and Pollution... Jun 2020The aim of the study was frequency analysis of GSTM1, GSTT1, and GSTP1 polymorphisms of glutathione S-transferase in the group of patients with prostate cancer and in a...
The aim of the study was frequency analysis of GSTM1, GSTT1, and GSTP1 polymorphisms of glutathione S-transferase in the group of patients with prostate cancer and in a control group of healthy individuals. Genomic DNA was isolated; molecular analysis of glutathione S-transferase M1 and T2 polymorphisms was performed using multiplex PCR and RFLP methods. The products of the PCR reaction were then visualized in agarose gel, and a statistical analysis of the results was performed. No statistically significant differences were found in the frequency of glutathione S-transferase polymorphisms between 66 patients with prostate cancer and the control group (64 healthy volunteers). The GSTM1 gene deletion was found in ca. 47% of patients with prostate cancer and in ca. 55% of the controls. The GSTT1 deletion was found in approximately 17% of patients and 14% of the controls. The distribution of GSTP1 Ile/Ile, Ile/Val, and Val/Val polymorphisms was ca. 51.5%, 39%, and 9% in the group of patients and 61%, 34%, and 5% in the control group, respectively. The results indicate that there is no relationship between glutathione S-transferase polymorphisms and prostate cancer in the study group, which is a novelty when compared with the previous work on the role of these genetic variants in the etiology of cancer.
Topics: Case-Control Studies; Genotype; Glutathione S-Transferase pi; Glutathione Transferase; Humans; Male; Poland; Risk Factors
PubMed: 32212077
DOI: 10.1007/s11356-020-08435-7 -
Hypertension (Dallas, Tex. : 1979) Sep 2021In the United States, the prevalence of chronic kidney disease in adults is ≈14%. The mainstay of therapy for chronic kidney disease is angiotensin-converting enzyme... (Review)
Review
In the United States, the prevalence of chronic kidney disease in adults is ≈14%. The mainstay of therapy for chronic kidney disease is angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, but many patients with chronic kidney disease still progress to end-stage kidney disease. Increased oxidative stress is a major molecular underpinning of chronic kidney disease progression. In humans, a common deletion variant of the glutathione-S-transferase μ-1 () gene, the null allele ()), results in decreased GSTM1 enzymatic activity and is associated with higher levels of oxidative stress. GSTM1 belongs to the superfamily of GSTs that are phase II antioxidant enzymes and are regulated by Nrf2 (nuclear factor erythroid 2-related factor 2). Cruciferous vegetables in general, and broccoli in particular, are rich in glucoraphanin, a precursor of sulforaphane that has been shown to have protective effects against oxidative damage through the activation of Nrf2. This review will highlight recent human and animal studies implicating the role of GSTM1 deficiency in hypertension and kidney disease, and its impact on the effects of cruciferous vegetables on kidney injury and disease progression, illustrating the significance of gene and environment interaction and a potential for targeted precision medicine in the treatment of kidney disease.
Topics: Animals; Brassicaceae; Diet; Glutathione Transferase; Humans; Hypertension; Isothiocyanates; Kidney Diseases; NF-E2-Related Factor 2; Precision Medicine; Sulfoxides
PubMed: 34455814
DOI: 10.1161/HYPERTENSIONAHA.121.16510 -
The Journal of Clinical Investigation Aug 2012In the 1960s, my lab was interested in understanding how bilirubin and other organic anions are transferred from the plasma through the liver cell and into the bile. We... (Review)
Review
In the 1960s, my lab was interested in understanding how bilirubin and other organic anions are transferred from the plasma through the liver cell and into the bile. We performed gel filtration of liver supernatants and identified two protein fractions, designated Y and Z, which bound organic anions including bilirubin, and thus we proposed that they were involved in hepatic uptake of organic anions from plasma. Subsequently, the Y and Z proteins responsible for this binding activity were purified, cloned, and sequenced. Y was identified as a member of the glutathione S-transferase (GST) protein family and Z found to be a member of the fatty acid–binding protein (FABP) family. These proteins have since been shown to have additional surprising roles, but understanding of their full role in physiology and disease has not yet been achieved.
Topics: Animals; Bilirubin; Fatty Acid-Binding Proteins; Glutathione Transferase; History, 20th Century; History, 21st Century; Humans; Liver; Research
PubMed: 23024981
DOI: 10.1172/jci64587